Compositions and methods for borocarbohydrate complexes

ABSTRACT

Borocarbohydrate complex containing compositions are presented that have an improved di-complex to boric acid ratio. In some embodiments, compositions are characterized by a di-complex to boric acid ratio of at least 5:1 and more typically at least 10:1 in liquid form, and at least 20:1 in dried form. In other embodiments, compositions are characterized by a minimum content of 80 wt % di-complex and a boric acid content of less than 15 wt %, and more typically less than 5 wt %. Contemplated compositions are thought to have improved biological activity and reduced content of undesired components.

FIELD OF THE INVENTION

The field of the invention is borocarbohydrate complexes, and especiallycompositions and methods for production of such complexes with improvedparameters.

BACKGROUND OF THE INVENTION

The background description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed invention, or that any publication specifically orimplicitly referenced is prior art.

For many years, calcium fructoborate (CF) has been a nutritionalsupplement of interest with many potential medicinal and therapeuticapplications. For example, CF has been shown to be an effectiveantioxidant (Scorei et. al., Biological Trace Element Research 107, no.2 (2005): 127-34), to be effective against cancer (Scorei and Popa,2010, Anti-Cancer Agents in Medicinal Chemistry 10, no. 4 (May 1, 2010):346-51), and to be a relatively effective modality for reducinginflammation associated with arthritis (Scorei et. al., Biological TraceElement Research 144, no. 1-3 (December 2011): 253-63). CF has also beenreported for use in the treatment of skin (U.S. Pat. No. 6,080,425) andin attempts to reduce the rate of hair growth (U.S. Pat. No. 5,985,842).

All publications identified herein are incorporated by reference to thesame extent as if each individual publication or patent application werespecifically and individually indicated to be incorporated by reference.Where a definition or use of a term in an incorporated reference isinconsistent or contrary to the definition of that term provided herein,the definition of that term provided herein applies and the definitionof that term in the reference does not apply.

Synthesis of CF has been described in various sources, and one exemplaryprotocol can be found in U.S. Pat. No. 6,924,269 in which 0.62 g boricacid was reacted with 3.60 g fructose in 10 ml of water, with subsequentneutralization using 1 g calcium carbonate under evolution of carbondioxide. While such process is at least conceptually simple on paper, itshould be recognized that there is substantial complexity involved uponcloser investigation. At the outset, commercially available fructoseexists in numerous isomeric forms, having five-membered heterocyclicrings (furanose) and six-membered (pyranose) heterocyclic rings, eachwith their own respective stereoisomeric configuration at the anomericcarbon atom, leading to respective alpha and beta forms. Still further,fructose may also exist in open-chain forms. To complicate matters, theboric acid molecule forms diester complex bonds with two hydroxyl groupsof a sugar molecule. As fructose has five hydroxyl groups (several ofthem in vicinal position), numerous ester products can be formed witheach of the stereoisomeric form of fructose. In addition, due to theremaining hydroxyl groups in the boric acid after esterification with afirst sugar molecule, further diester complex bonds can be formed with asecond sugar molecule, at various positions. Exemplary stereoisomers forfructose are shown in Panel A of FIG. 1, while exemplary mono-complexesare depicted in Panel B of Figure land exemplary di-complexes aredepicted in Panel C of FIG. 1. Thus, and not surprisingly, only verylittle information on reaction dynamics and specific product formationis known for boro-carbohydrate complexes.

For example, Edwards et al. (Journal of Food Research 3, no. 3 (May 15,2014)) report an NMR analysis of fructoborate complexes and theirdistribution of stereoisomers along with stability data, and Makkee et.al. (Recueil Des Travaux Chimiques Des Pays-Bas 104, no. 9 (Sep. 2,2010): 230-35) describe selected processes for preparation of boratecomplexes with saccharides in small scale under selected reactionconditions in an attempt to characterize formation of various forms.However, all or almost all of the conditions that were described asproviding CF as a di-complex suffered from very low yields and/orsubstantial residual quantities of boric acid, which is generallyundesirable. For example, Makkee et al. showed that the di-complex canbe favored in reactions at high pH that utilize a large (5:1 or 10:1)fructose to boron molar ratio, however the overall yield of the CFdi-complex is very poor, leaving excess quantities of free fructosewhich leads to a significant dilution of the desired product. On theother hand, where the fructose to boron molar ratio was reduced, freeboric acid content almost exponentially increased at concurrent loss ofdi-complex versus mono-complex. Residual boric acid is also veryundesirable due to its potential toxicity and other possibleinterference with biological molecules (e.g., boric acids are known toact as inhibitor to certain enzymes (e.g., urease) or Rho family ofGTP-binding proteins). Such lack of specific guidance is especiallydisappointing as it has been speculated that the di-complex is thebiologically most relevant and therefore most desirable form of CF.

Thus, while CF and other carbohydrate complexes are well known in theart, there is still a need for a process that results in a high-yield ofdi-complex calcium fructoborate or other boro-carbohydrate complexes.Viewed from a different perspective, it would be desirable to have aprocess that provides a composition comprising calcium fructoborate orother boro-carbohydrate complex with low (e.g., ≦10 wt %) residual freeboric acid in the product. In the same way, it would be desirable tohave a process that provides a composition with calcium fructoborate oranother boro-carbohydrate complex without large amounts (e.g., ≧30 wt %)of residual fructose or other carbohydrate in the product. Finally, andviewed from yet another perspective, it would be desirable to have aprocess that provides a composition with a di-complex to free boric acidratio that is at least 10:1, more preferably at least 15:1, and mostpreferably at least 20:1.

SUMMARY OF THE INVENTION

The inventive subject matter is directed to various borocarbohydratecomplex-containing compositions and methods of their production. Inespecially noteworthy aspects of the inventive subject matter, theborocarbohydrate complex-containing compositions have a very highcontent of di-complex, a very low content of unreacted boric acid, andare obtained at remarkably high yields.

In one aspect of the inventive subject matter, The inventors contemplatea method of producing a composition that comprises borocarbohydratecomplexes in an amount of at least 65 wt %, wherein the borocarbohydratecomplexes include di-complexes and mono-complexes, wherein thecomposition further comprises boric acid, and wherein the di-complex andthe boric acid are present in a ratio of at least 10:1. Particularlycontemplated methods include a step of selecting a molar ratio between acarbohydrate and the boric acid of at least 1.8:1, and a further step ofselecting a preparative scale for the reaction of at least 1000 ml. Thecarbohydrate is then reacted with the boric acid at the ratio and thescale to thereby form the carbohydrate complexes. In most embodiments, acation is added to form a salt of the carbohydrate complexes.

In some aspects, the step of reacting forms the carbohydrate complexesin an amount of 70 wt %, and/or the molar ratio between the carbohydrateand the boric acid is between 1.8:1 and 2.4:1, and/or the preparativescale for the reaction is at least 5,000 ml. Therefore, it is alsocontemplated that the di-complex and the boric acid are present in aratio of at least 15:1, or in a ratio of at least 20:1. Most typically,the composition is a liquid composition, and/or the carbohydrate isfructose, and/or the cation is a calcium cation or a magnesium cation.It is further contemplated that the composition has a pH of less than6.0.

Viewed from a different perspective, the inventors also contemplate amethod of producing a composition comprising borocarbohydrate complexeshaving a borocarbohydrate di-complex to boric acid ratio of at least5:1. In such methods, a molar ratio between the carbohydrate and theboric acid of at least 1.6:1 is selected and a preparative scale for thereaction of at least 200 ml is selected. The carbohydrate is thenreacted with the boric acid and a compound that comprises a cation at anacidic pH and at the ratio and the scale to so form the carbohydratecomplexes, wherein the carbohydrate complexes form a salt with thecation.

In most aspects, the molar ratio between the carbohydrate and the boricacid is between 1.8:1 and 2.4:1, and/or the preparative scale for thereaction is at least 1,000 ml, and/or the acidic pH is a pH of less than6.0. Most typically, the borocarbohydrate complexes are present in thecomposition in an amount of at least 60 wt %, and/or theborocarbohydrate di-complex to boric acid ratio is at least 10:1. Thecompound that comprises a cation is in many embodiments an alkalinemetal hydroxide, an earth alkaline metal hydroxide, an alkaline metalcarbonate, or an earth alkaline metal carbonate, and/or the carbohydrateis fructose.

Therefore, the inventors also contemplate a method of increasingdi-complex content in a preparative reaction having a first reactionscale to form a composition comprising at least 65 wt % borocarbohydratecomplexes, wherein the borocarbohydrate complexes are a mixture ofdi-complexes and mono-complexes. Such methods will typically include astep of selecting a molar ratio between the carbohydrate and the boricacid of at least 1.4:1, and a further step of increasing the firstreaction scale (e.g., at least 200 ml) to a second reaction scale, andreacting the carbohydrate and the boric acid at the ratio at the secondreaction scale (e.g., at least 1,000 ml) to thereby increase thedi-complex content in the second reaction scale as compared to the firstreaction scale.

In preferred embodiments the carbohydrate is fructose, and/or the stepof increasing the first reaction scale to the second reaction scale alsodecreases unreacted boric acid in the second reaction scale as comparedto the first reaction scale. In most embodiments, the molar ratiobetween the carbohydrate and the boric acid is between 1.8:1 and 2.4:1.Where desired, water can be removed from the composition (e.g., viafreeze-drying or spray drying).

Thus, viewed from a different perspective, and in a method of producinga composition comprising borocarbohydrate complexes and boric acid,wherein the borocarbohydrate complexes are a mixture of di-complexes anda mono-complexes, an improvement may comprise a step of reacting acarbohydrate with boric acid at an acidic pH and at a molar ratiobetween the carbohydrate and the boric acid of at least 1.8:1, whereinthe step of reacting is performed at a preparative scale of at least1000 ml to thereby achieve a ratio of di-complex to residual boric acidof at least 10:1.

Most typically, the carbohydrate is fructose, and/or the pH is less than6.0, and/or the molar ratio between the carbohydrate and the boric acidis between 1.8:1 and 2.4:1. Therefore, the ratio of di-complex toresidual boric acid of at least 15:1 or at least 20:1. As before, it iscontemplated that such improvements may include a step of removing waterfrom the composition.

In yet another aspect of the inventive subject matter, a method ofproducing a composition with a boric acid content of equal or less than15 wt % is contemplated, wherein the composition comprises at least 70wt % borocarbohydrate complexes, and wherein the borocarbohydratecomplexes are a mixture of di-complexes and mono-complexes. Such methodswill include a step of selecting a molar ratio between the carbohydrateand the boric acid such that the carbohydrate is in molar excess overthe boric acid, and a further step of selecting a preparative scale forthe reaction of at least 1000 ml, and a still further step of reactingthe carbohydrate and the boric acid at an acidic pH to thereby producethe composition with the boric acid content of equal or less than 15 wt%.

In such methods, it is contemplated that the boric acid content of thecomposition is equal or less than 10 wt % or equal or less than 5 wt %,and/or that the molar ratio between the carbohydrate and the boric acidis between 1.6:1 and 2.2:1, and/or that the acidic pH is a pH of lessthan 6.0.

Consequently, the inventors also contemplate a liquid composition thatcomprises a plurality of borocarbohydrate complexes and boric acid,wherein the borocarbohydrate complexes are a mixture of a di-complex anda mono-complex, and wherein the di-complex is present in the compositionin an amount of at least 75 wt % and wherein the boric acid constitutesless than 13 wt % of the composition.

Most typically, the ratio of the di-complex to the mono-complex in themixture is between 10:1 and 12:1, and/or the di-complex is present inthe composition in an amount of at least 80 wt % or at least 85 wt %,while unreacted boric acid is present in the composition in an amount ofless than 10 wt %, or less than 5.0 wt %.

Viewed from a different perspective, the inventors also contemplate aliquid composition having an acidic pH and comprising a borocarbohydratedi-complex and boric acid, wherein the borocarbohydrate di-complex andthe boric acid are present in a ratio of at least 10:1. The acidic pH insuch compositions is a pH of less than 6.0, and/or the borocarbohydratedi-complex and the boric acid are present in a ratio of at least 15:1,or at least 20:1, while the unreacted boric acid is present in an amountof less than 10 wt % or less than 5 wt %. It is further contemplatedthat in such compositions the borocarbohydrate di-complex is present inan amount of at least 80 wt %.

In yet another aspect of the inventive subject matter, the inventorsalso contemplate a liquid composition comprising a borocarbohydratedi-complex, a borocarbohydrate mono-complex and boric acid, wherein aratio between the borocarbohydrate di-complex and the borocarbohydratemono-complex is at least 10:1, and wherein the boric acid is present inthe composition in an amount of equal or less than 10 wt %.

The ratio between the borocarbohydrate di-complex and theborocarbohydrate mono-complex in such compositions is at least 15:1, orat least 20:1, and/or the ratio between the borocarbohydrate di-complexand the borocarbohydrate mono-complex is at least 25:1, while in furtheraspects the boric acid is present in the composition in an amount ofequal or less than 7.5 wt %, or less than 5.0 wt %. Most typically, theliquid composition has a pH of less than 6.0.

Therefore, the inventors also contemplate a liquid reaction mixturehaving an acidic pH comprising a carbohydrate, boric acid, andborocarbohydrate complexes, wherein the borocarbohydrate complexes are amixture of di-complexes and mono-complexes, and wherein the di-complexesand the boric acid are present in a ratio of at least 5:1, and wherein aratio of the borocarbohydrate complexes to the carbohydrate is between1.5 and 4.5. Most typically, the ratio of the borocarbohydrate complexesto the carbohydrate is between 2.0 and 3.5, and/or the pH is less than6.0 while the liquid reaction mixture has a volume of at least 200 ml.

Moreover, the inventors also contemplate a composition comprising aborocarbohydrate di-complex and unreacted boric acid, wherein theborocarbohydrate di-complex and the boric acid are present in thecomposition in a ratio of at least 10:1 in liquid form and at least 20:1in dried form. In such compositions, the borocarbohydrate di-complex andthe boric acid are present in the composition at a ratio of at least15:1 in liquid form and at least 22:1 in dried form, and/or the boricacid is present in the composition in an amount of less than 10 wt %, orless than 5.0 wt %.

In view of the above, a composition is also contemplated comprising aborocarbohydrate complex that is produced by a process having the stepsof (a) selecting a molar ratio between the carbohydrate and the boricacid of at least 1.6:1; (b) selecting a preparative scale for thereaction of at least 1000 ml; and (c) reacting the carbohydrate and theboric acid at an acidic pH to thereby obtain a composition thatcomprises a borocarbohydrate di-complex and boric acid at a ratio of atleast 5:1.

Most typically, the molar ratio between the carbohydrate and the boricacid is between 1.8:1 and 2.2:1, and/or the acidic pH is a pH of lessthan 6.0, and/or the composition comprises the borocarbohydratedi-complex and the boric acid at a ratio of at least 10:1 or at least15:1.

Various objects, features, aspects and advantages of the inventivesubject matter will become more apparent from the following detaileddescription of preferred embodiments, along with the accompanyingdrawing figures in which like numerals represent like components.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows exemplary stereoisomeric forms of fructose (Panel A),fructoborate mono-complexes (Panel B), and fructoborate di-complexes(Panel C).

FIGS. 2A and 2B show graphs for densitometry readings of TLC tracks.Tracks in FIG. 2A represent individual reactions of fructose and boricacid with molar ratios ranging from 1:10 to 1:1, and tracks in FIG. 2Brepresent individual reactions of fructose and boric acid with molarratios ranging from 1:1 to 10:1.

FIGS. 3A to 3F illustrate exemplary results for selected productparameters at a 200 ml scale and molar ratios of fructose to boric acidbetween 1:1 and 3:1. FIG. 3A lists di-complex (‘di-ester’) formation asa function of molar ratio; FIG. 3B shows the ratio of di-complex tounreacted boric acid as a function of molar ratio; FIG. 3C providescompositional information about stereochemical aspects in fructoboratecomplexes as a function of molar ratio; FIG. 3D is a line graph showingcorresponding compositional information about stereochemical aspects inunreacted fructose as a function of molar ratio; FIG. 3E illustratesyields of total fructose complexes (mono- and di-complexes) relative tounreacted fructose as a function of molar ratio; FIG. 3F is a line graphillustrating the ratio of total fructose complexes to unreacted fructoseas a function of molar ratio.

FIGS. 4A to 4B illustrate exemplary results for selected productparameters at a 5,000 ml scale and molar ratios of fructose to boricacid between 1.4:1 and 2.2:1. FIG. 4A illustrates yields of totalfructose complexes (mono- and di-complexes) relative to unreactedfructose as a function of molar ratio; FIG. 4B is a line graphillustrating the ratio of total fructose complexes to unreacted fructoseas a function of molar ratio.

FIGS. 5A to 5E depict exemplary results for selected product parametersat escalating production scales and variable molar ratios of fructose toboric acid. FIG. 5A is a line graph showing a decrease of free(unreacted) boric acid as a result of scale up at the same molar ratiosover a range of preset molar ratios. FIG. 5B is a line graph showing anincrease of di-complex as a result of scale up at the same molar ratiosover a range of preset molar ratios. FIG. 5C is a line graph showingthat the quantities of mono-complex is substantially unaffected by scaleup at the same molar ratios over a range of preset molar ratios. FIG. 5Dis a bar graph showing an increase of the ratio of di-complex to freeboric acid as a result of scale up and an exacerbated increase of thesame ratio as a function of molar ratios between fructose and boricacid. FIG. 5E is a bar graph indicating that the ratio of di-complex tomono-ester is substantially unaffected by scale up and molar ratiosbetween fructose and boric acid.

FIGS. 6A to 6B show exemplary results for selected product parameters ofreconstituted compositions after water had been removed using a fixedmolar ratio between fructose and boric acid. FIG. 6A shows ratios ofdi-complex to free boric acid in liquid, reconstituted freeze-dried(FD), and reconstituted spray-dried (SD) forms as a function ofproduction scale. FIG. 6B shows ratios of di-complex to free boric acidin various production scales as a function of state (liquid,reconstituted freeze-dried (FD), and reconstituted spray-dried (SD)).

DETAILED DESCRIPTION

The inventors have discovered various methods and conditions that allowproduction of borocarbohydrate complex-containing compositions with highcontent of di-complexes, very low content of unreacted boric acid, andlow quantities of unreacted fructose, all at remarkably high yields.

For example, in some aspects of the inventive subject matter, and asdescribed in more detail below, total carbohydrate complexes could beproduced at yields of ≧60 wt %, ≧65 wt %, ≧70 wt %, or ≧75 wt %. Inother aspects of the inventive subject matter, and as also described inmore detail below, unreacted boric acid was limited to quantities of ≦10wt %, ≦8 wt %, ≦6 wt %, or ≦4 wt %. In yet further aspects of theinventive subject matter, and as described in more detail below, theyields of the di-ester were remarkably high, for example, at a di-esterto mono-ester ratio of at least 8:1, at least 9:1, at least 10:1, or atleast 11:1, and/or at a di-ester to unreacted boric acid of at least9:1, at least 10:1, at least 15:1, at least 20:1, or at least 25:1 asalso shown in more detail below. Therefore, in still other aspects ofthe inventive subject matter, total carbohydrate complexes can beproduced with low residual quantities of carbohydrate, at for example,≦35 wt %, ≦30 wt %, ≦25 wt %, or ≦20 wt % unreacted carbohydrate. Unlessspecified otherwise, all percentages are indicated as wt % of the totalof all reaction products and unreacted reagents.

Despite the seemingly simple reaction of boric acid and carbohydrates toform esters, the inventors discovered that numerous reaction parametershave unexpected and significant impact on various aspects of productformation, and especially on quantities of di-complex, overall yield ofborocarbohydrate complexes, and residual (unreacted) boric acid. Forexample, while a molar excess of boric acid over fructose generallyincreases overall complex formation, inverting these molar proportions(e.g., using slight molar excess of fructose over boric acid) lead to anoptimum area of di-complex formation with apparent saturation startingat a ratio of about 1.8. Even more unexpectedly, increasing the molarratio of fructose to boric acid (between 1:1 and 3:1) revealed that at aratio of about 2.2-2.4:1 free boric acid was at a minimum, but thatthere was a balance point in maximizing yield of complex formation(where a lower fructose to boric acid ratio was better) and free boricacid (where a higher fructose to boric acid ratio was better).Additionally, the inventors unexpectedly discovered that a simplescale-up of the reaction at particular molar ratios of carbohydrate toboric acid ratio using otherwise identical process conditions decreasedunreacted boric acid and also increased the yield of the di-complex(especially at molar ratios of carbohydrate to boric acid ratio of 1.4:1to 2.2:1). Oddly, the formation of mono-complexes was substantiallyunaffected.

In another unexpected finding on scale-up, the inventors also discoveredthat the ratio of di-complex to free boric acid was almost entirelyinsensitive to scale-up where the molar ratios of fructose to boric acidwas below 1.6:1 (e.g., 1.4:1 to 1.6:1), was only slightly affected at amolar ratio of fructose to boric acid of 1.8:1, and was substantiallyaffected (e.g., almost linear at 2.0:1) with an apparent optimum 5 Lscale for 2.2:1 as also shown in more detail below.

It should be appreciated that while specific examples below are providedwith respect to fructose as the carbohydrate, numerous othercarbohydrates are also deemed suitable for use herein, and especiallynutritionally acceptable carbohydrates. Thus, alternative carbohydratesgenerally include various hexoses and pentoses, which may be in aldoseor ketose form, and which may be (when in ring form) present as furanoseor pyranose carbohydrate. Viewed from a different perspective, suitablecarbohydrates include various monosaccharides, disaccharides,oligosaccharides, and polysaccharides, all of which may be natural orsynthetic. Exemplary carbohydrates therefore include glucose, fructose,galactose, sucrose, maltose, lactose, etc. Moreover, alternativecompounds to carbohydrates include various polyols, and especiallynutritionally and/or pharmaceutically acceptable polyols, as well asother nutritionally and/or pharmaceutically acceptable compounds withgerminal or 1,3-diol groups. While not limiting to the inventive subjectmatter, it is also contemplated that the carbohydrates may include oneor more isotopic atoms (e.g., ¹³C, ¹⁴C, ²H, ¹⁷O or ¹⁸O). Similarly, itis generally preferred that the boron in the borocarbohydrate complexesis provided in the form of boric acid, and most typically in the form ofan aqueous solution. However, in other aspects of the inventive subjectmatter, boron may be provided as borax solution, or as a boronic acid.

In many embodiments, the preparation of the borocarbohydrate complexesis based on reacting fructose in solution with boric acid for a timesufficient to allow the reaction to run to completion and/or thereaction mixture to become clear (e.g., at least 30 min, at least 60min, or at least 90 min). After the reaction is completed, theborocarbohydrate complexes can be charge neutralized with acation-containing compound, which is preferably an alkaline metalhydroxide, an earth alkaline metal hydroxide, an alkaline metalcarbonate, and/or an earth alkaline metal carbonate (e.g., calciumcarbonate). Most typically, the cation-containing compound is added inan amount that is between an equimolar amount (with respect to boricacid) and 10% of the molar amount of boric acid, most typically between0.7 and 0.3 (e.g., 0.5) times the molar amount of boric acid. Where thecation-containing compound is a hydroxide or carbonate, it is in mostaspects preferred that the cation-containing compound is added slowly(e.g., over a period of at least 10 min, at least 20 min, or at least 30min), and where appropriate in multiple batches (e.g., at least two,three or four, etc.). The so prepared liquid composition can then befurther combined with other components, or compounded with one or morebeverages. Alternatively, water can be at least partially removed toobtain a concentrate or dry product (e.g., via freeze drying or spraydrying) that can then be used as or compounded with a nutritionalsupplement.

Experiments and Results

Unless indicated otherwise, all reactions were performed at theindicated scale and molar ratios between fructose and boric acid byfirst dissolving fructose in water at a temperature of 20-25° C. Solidboric acid is then added at the selected molar ratio, and the mixture isreacted under continuous stirring for 90 minutes at a temperature of20-25° C. Where desired, CaCO₃ is then added in an amount that is 50% ofthe molarity of the boric acid over a period of 30 minutes in threeequal batches under continuous stirring (e.g., where 1 mol of boric acidwas used, 0.5 mol CaCO₃ was used). The pH of the reaction was typicallyneutral to moderately acidic, and in most cases at a pH of less than6.0.

Liquid-state ¹¹B, ¹³C, and ¹H NMR was performed on a Varian Mercury300MVX NMR spectrometer equipped with a 5 mm Varian ATB Probe atresonance frequencies of 96.14 MHz (¹¹B), 75.36 MHz (¹³C) and 299.67 MHz(¹H), respectively. ¹¹B spectra were acquired with a 45 degree tip anglepulse width, a relaxation delay of 0.2 seconds, an acquisition time of80 ms with 8K points acquired with a spectral width of 100 kHz, and 1024pulses were averaged. The data was zero filled to 65K points. The ¹³CNMR was acquired with a 30 degree tip angle pulse width, a relaxationdelay of 5 seconds, 0.96 second acquisition time, with 24K pointsacquired with a spectral width of 25 kHz, and 10-12,000 pulses wereaveraged. The data was zero filled to 131K points. The ¹H NMR spectrawere obtained with a 30 degree pulse angle, a relaxation delay of 2seconds, a 4.448 second acquisition time, with 32K points acquired overa spectral width of 7.2 kHz, and 128 pulses were averaged. The data waszero-filled to 131K points. The data was acquired in a quantitativemanner with inverse gated decoupling of protons during the acquisitionof the ¹¹B and ¹³C experiments. All samples were dissolved in D₂O(Cambridge Isotope Laboratories). No pH adjustments were performed onthe samples after dissolution.

Solid-State ¹³C (50.30 MHz), ¹¹B (64.17 MHz) NMR spectra were obtainedon a Varian UnityPlus-200 NMR spectrometer equipped with a DotyScientific 7 mm Supersonic CP-MAS probe. Magic angle spinning (MAS)speeds of around 6 kHz were employed. The ¹³C NMR data was acquiredusing cross polarization which prepares the magnetization on the protonsinitially and then transfers the spin locked magnetization to the ¹³Cnuclei. The advantage of this experiment is the fact that it isperformed at the spin-lattice relaxation rate (T1) of protons in thesample which is considerably shorter than the T1 of ¹³C nuclei in thesame sample. Thus, one obtains a significant enhancement of the ¹³Csignal from the polarization transfer and can pulse at a shorterpulse-repetition rate. The ¹³C CP-MAS experiment on calcium fructoboratecomplex was performed with a 1 ms variable amplitude contact time, an 8second relaxation rate, and an acquisition time of 25.6 ms, with 1Kpoints being acquired over a spectral with of 40 kHz, and 4096 pulseswere averaged. The exceptions to these acquisition parameters were thoseused for pure crystalline fructose. The ¹¹B NMR spectra were acquiredwith MAS and with the sample remaining static in the NMR probe. Theexperiments were acquired with a central transition selective pulsewidth, a 0.2 second relaxation time, with 1K points being acquired in anacquisition time of 10.2 ms, and with a spectral width of 100 kHz.

Samples were observed directly after they were received, after they hadbeen thermally treated in a Duratech TCON dry bath system (capable ofholding temperatures to +/−0.1° C.), or as calibration standards whichwere made by mixing accurately weighed samples of calcium fructoboratewith magnesium stearate or maltodextrin. Samples for solid-state NMRwere weighed to the nearest 0.1 mg on a Sartorius GD-503-NTEPmicrobalance after they were packed into the MAS rotor.

Initial studies had shown that overall borocarbohydrate complexformation was favored under substantial molar excess of boric acidrelative to fructose as can be seen from FIGS. 2A and 2B. Moreparticularly, FIG. 2A illustrates optical densitometry readings from aTLC plate onto which were spotted aliquots of small scale reactionvolumes (e.g., 2 ml) with decreasing molar ratios between fructose andboric acid. Reading the lanes from front to back, the first lane isfructose control, while the following next 10 lanes reflect a decreasestarting at 10:1 (fructose to boric acid) to 1:1 (fructose to boricacid). As is readily evident, appreciable quantities of total complexformation begin to develop at equimolar ratios (see last lane).Similarly, FIG. 2B illustrates optical densitometry readings from a TLCplate onto which were spotted aliquots of small scale reaction volumes(e.g., 2 ml) with increasing molar ratios between boric acid andfructose. Again, reading the lanes from front to back, the first lane isfructose control, while the following next 10 lanes reflect an increasestarting at 1:1 (fructose to boric acid) to 1:10 (fructose to boricacid). As can be seen, appreciable total complex formation is favored ata molar ratio of 1:2 (fructose to boric acid), and is nearlyquantitative at a molar ration of 1:5 (fructose to boric acid). Thus,under the conditions observed, molar excess of boric acid drove theformation of total borocarbohydrate complex yield.

In an effort to further investigate the reaction conditions and productcompositions, the inventors performed numerous experiments at variousproduction scales and various molar ratios between the carbohydrate(e.g., fructose) and boric acid. Quite unexpectedly, the inventors foundthat the specific product composition is substantially affected by atleast the molar ratios between the carbohydrate (e.g., fructose) andboric acid and/or the production scale. Contrary to the skilledartisan's approach of using a high boric acid to carbohydrate ratio toso increase overall yield of the borocarbohydrate complex as suggestedby the data in FIGS. 2A and 2B, the inventors discovered that byselection of the appropriate molar ratio between the carbohydrate andthe boric acid an enhanced yield of di-complex can be obtained atconcurrent low quantities of unreacted boric acid.

For example, the inventors modified the molar ratio between thecarbohydrate (here: fructose) and boric acid over a relatively largerange from an equimolar ratio to a 3:1 molar excess of fructose to boricacid at a 200 ml production scale. Notably, based on quantitative ¹¹BNMR analysis and as can be clearly seen in Table 1 below, quantities ofunreacted boric acid significantly decreased with increasing molar ratio(in the range from 1.0:1 to 2.4:1), and then moderately rose withfurther increasing molar ratio (in the range from 2.6:1 to 3.0:1. Thus,it should be appreciated that an increase in the molar ratio between thecarbohydrate (here: fructose) and boric acid over a range of at least1.8:1 to 2.6:1 had the unexpected technical effect of decreasingquantities of unreacted boric acid. Conversely, the quantities of thedi-complex increased as a function of an increasing molar ratio betweenthe carbohydrate (here: fructose) and boric acid over a relatively largerange from an equimolar ratio to a 3:1 molar excess of fructose to boricacid at a 200 ml production scale, possibly with a saturation effectstarting at a molar ratio of about 1.8:1. Thus, compositions withespecially high di-complex content could be obtained at molar ratios atand above 1.6:1 or 1.8:1. Therefore, an increase in the molar ratiobetween the carbohydrate (here: fructose) and boric acid starting at1.6:1 or 1.8:1 had the unexpected technical effect of increasingquantities of di-ester. Remarkably, the increase in molar ratio betweenfructose and boric acid had little to no effect on the quantities ofmono-ester produced by the reaction.

FIG. 3A exemplarily illustrates the dramatic increase in di-ester yieldas a function of increasing molar ratio between the carbohydrate (here:fructose) and boric acid. The ratio of di-ester to unreacted boric acidis exemplarily depicted in FIG. 3B, where the optimum range for theratio is between 1.8:1 and 2.6:1.

TABLE 1 Molar Borate Di-Ester Mono-ester Di-ester/Borate Ratio (wt %)(wt %) (wt %) Ratio Volume 200 ml 1.0:1 44.34 47.84 7.81 1.08 1.2:136.42 58.26 5.32 1.60 1.4:1 20.32 73.28 6.40 3.61 1.6:1 13.38 79.12 7.505.91 1.8:1 8.46 83.84 7.70 9.91 2.0:1 9.28 84.04 6.68 9.05 2.2:1 6.4685.86 7.67 13.28 2.4:1 6.64 87.01 6.35 13.10 2.6:1 8.50 86.19 5.31 10.142.8:1 10.78 84.33 4.89 7.82 3.0:1 10.30 85.02 4.68 8.25

Remarkably, ¹³C NMR analysis also revealed that an increase in the molarratio of carbohydrate (here: fructose) to boric acid decreased totalcomplex (di-plus mono-complex) formation most significantly for thealpha-fructofuranose form, moderately for the beta-fructofuranose form,and negligibly or not for the beta-fructopyranose form as can be takenfrom Table 2 below. Also, the most pronounced decrease in total complexforms for the alpha-fructofuranose form and the beta-fructofuranose formstarted at a ratio of 1.6:1 or 1.8:1, which appears to be acounter-trend to the specific increase in di-ester formation atcomparable ratios. Thus, an increase of the molar ratio of carbohydrate(here: fructose) to boric acid above 1.6:1 or 1.8:1 had the surprisingtechnical effect of decreasing total complexes in alpha-fructofuranoseform and to some extent beta-fructofuranose form. FIG. 3C is a graphicrepresentation of the results of Table 2.

TABLE 2 Molar a-FF-B-Complex b-FF-B-Complex b-FP-B-Complex Ratio (wt %)(wt %) (wt %) Volume 200 ml 1.0:1 50.58 18.42 17.02 1.2:1 47.15 18.3113.02 1.4:1 46.44 17.68 11.47 1.6:1 48.44 18.79 14.20 1.8:1 45.00 17.7912.89 2.0:1 44.19 18.93 13.02 2.2:1 43.00 18.10 9.97 2.4:1 41.60 17.759.12 2.6:1 38.97 17.88 7.34 2.8:1 37.93 16.21 6.80 3.0:1 36.05 16.495.70

Likewise, ¹³C NMR analysis revealed that an increase in the molar ratioof carbohydrate (here: fructose) to boric acid increased unreactedcarbohydrate (here: fructose) most significantly for thebeta-fructopyranose form, moderately for the beta-fructofuranose form,and negligibly or not for the alpha-fructofuranose form as can be takenfrom Table 3 below. Once more, the most pronounced increase in unreactedcarbohydrate for the beta-fructopyranose form and thebeta-fructofuranose form started at a ratio of 1.6:1 or 1.8:1.Therefore, an increase of the molar ratio of carbohydrate (here:fructose) to boric acid above 1.6:1 or 1.8:1 had the unexpectedtechnical effect of the unreacted carbohydrate for thebeta-fructopyranose and the beta-fructofuranose forms as is also shownin FIG. 3D.

TABLE 3 Molar a-FF b-FF b-FP Ratio (wt %) (wt %) (wt %) Volume 200 ml1.0:1 0.66 4.84 8.49 1.2:1 1.19 6.09 14.24 1.4:1 2.65 6.55 15.21 1.6:11.35 4.96 12.26 1.8:1 2.80 6.95 14.57 2.0:1 2.20 6.88 14.79 2.2:1 2.657.14 19.14 2.4:1 1.54 7.80 22.19 2.6:1 3.02 8.11 24.67 2.8:1 2.46 9.0727.53 3.0:1 1.83 9.93 30.00

Tables 4 below demonstrates that the yield of fructose complexation isin inverse relation to increasing molar ratio of the carbohydrate toboric acid ratio. Notably, the yield of total fructose in complex aswell as the specific yield (total fructose in complex relative to freetotal fructose) decreased with increasing molar ratio of thecarbohydrate to boric acid ratio in counter trend to the yield fordi-complex formation. Thus, it should be appreciated that variouscompositions with high specific di-complex yield at relatively highoverall complex yields will typically be achieved where the reaction isperformed at a molar ratio of the carbohydrate to boric acid of about1.6:1 to 2.4:1. Selected results of Table 4 are exemplarily depicted inFIGS. 3E and 3F.

TABLE 4 Molar Total Fructose in Free Fructose Complex:Free Ratio Complex(wt %) (wt %) Ratio Volume 200 ml 1.0:1 86.02 13.98 6.15 1.2:1 78.4821.52 3.65 1.4:1 75.59 24.41 3.10 1.6:1 81.44 18.56 4.39 1.8:1 75.6824.32 3.11 2.0:1 76.14 23.86 3.19 2.2:1 71.07 28.93 2.46 2.4:1 68.4731.53 2.17 2.6:1 64.20 35.80 1.79 2.8:1 60.94 39.06 1.56 3.0:1 58.2441.76 1.39

Such trend was also observed to be true where the production scale wasincreased from 200 ml to 1000 ml, to 5,000 ml, and even to 2,000 L as isshown in Table 5 below and selected results of Table 5 are shown in thegraphs of FIGS. 4A and 4B.

TABLE 5 α-FF-B- β-FF-B- β-FP-B- Molar Ratio Complex Complex Complex α-FFβ-FF β-FP (scale) Wt % Wt % Wt % Wt % Wt % Wt % 1:01 (1L) 50.6 18.4 17.00.7 4.8  8.5 1.2:1 (1L) 47.1 18.3 13.0 1.2 6.1 14.2 1.4:1 (1L) 46.4 17.711.5 2.6 6.5 15.2 1.6:1 (1L) 48.4 18.8 14.2 1.3 5.0 12.3 1.8:1 (1L) 45.017.8 12.9 2.8 6.9 14.6 2:01 (1L) 44.2 18.9 13.0 2.2 6.9 14.8 2.2:1 (1L)43.0 18.1 10.0 2.6 7.1 19.1 2.4:1 (1L) 41.6 17.7  9.1 1.5 7.8 22.2 2.6:1(1L) 39.0 17.9  7.3 3.0 8.1 24.7 2.8:1 (1L) 37.9 16.2  6.8 2.5 9.1 27.53:01 (1L) 36.0 16.5  5.7 1.8 9.9 30.0 1.4:1 (5L) 48.8 17.5 16.3 0.9 5.910.6 1.6:1(5L) 46.5 19.2 16.3 0.9 5.9 10.6 1.8:1 (5L) 47.8 17.6 12.9 1.56.2 13.9 2:1 (5L) 44.6 18.3  9.8 1.4 7.2 18.6 2.2:1 (5L) 43.9 16.5  9.11.4 8.0 21.1 2.0:1 (2000L)

Table 6 further provides experimental data for the yield of totalfructose in complex versus free fructose over a variety of molar ratiosand production scales.

TABLE 6 Molar Ratio Total Fructose in Free Fructose (scale) Complex Wt %Wt % 1:01 (1 L) 86.0 14.0 1.2:1 (1 L) 78.5 21.5 1.4:1 (1 L) 75.6 24.41.6:1 (1 L) 81.4 18.6 1.8:1 (1 L) 75.7 24.3 2:01 (1 L) 76.1 23.9 2.2:1(1 L) 71.1 28.9 2.4:1 (1 L) 68.5 31.5 2.6:1 (1 L) 64.2 35.8 2.8:1 (1 L)60.9 39.1 3:01 (1 L) 58.2 41.8 1.4:1 (5 L) 82.5 17.5 1.6:1 (5 L) 82.517.5 1.8:1 (5 L) 78.4 21.6 2:1 (5 L) 72.7 27.3 2.2:1 (5 L) 69.5 30.52.0:1 (2000 L) 77.8 22.2

In yet another unexpected result during scale-up of the productionvolume, the inventors discovered that the production scale hadsubstantial effect on both, the quantities of unreacted boric acid andthe yield of di-ester formation for a given molar ratio. In short, andas can be taken from the data in Table 7, an increase in productionscale at a given molar ratio of fructose to boric acid increased theyield of di-complex, while the same increase in production scale at agiven molar ratio of fructose to boric acid decreased unreacted boricacid. Viewed from another perspective, and all other parameters beingthe same, the inventors discovered that an increase in production scaleincreased di-complex yield and decreased unreacted boric acid, whileleaving the mono-ester substantially unaffected. FIG. 5A exemplarilyshows this trend for unreacted boric acid, while FIG. 5B illustrates thetrend for di-ester formation, and FIG. 5C shows results for themono-ester yields. Thus, it should be appreciated that scale-up (withall other parameters being identical) had a rather unexpected technicaleffect of increasing the yield of di-complex, and decreasing quantitiesof unreacted boric acid.

TABLE 7 Borate Di-Ester Mono-ester Molar 200 2000 200 2000 200 2000Ratio ml 1 L 5 L L ml 1 L 5 L L ml 1 L 5 L L 1.0:1 44.34 47.84 7.821.2:1 36.42 58.26 5.32 1.4:1 20.32 20.10 17.40 73.28 73.90 74.00 6.406.00 8.60 1.6:1 13.38 12.10 11.00 79.12 80.20 79.80 7.50 7.70 9.20 1.8:1 8.46  7.90  6.80 83.84 84.00 85.90 7.70 8.10 7.30 2.0:1  9.28  6.40 4.50 3.20 84.04 85.50 87.60 88.80 6.68 8.10 7.90 8.00 2.2:1  6.46  4.30 5.00 85.86 87.50 88.50 7.67 8.20 6.50 2.4:1  6.64 87.01 6.35 2.6:1 8.50 86.19 5.31 2.8:1 10.78 84.33 4.89 3.0:1 10.31 85.02 4.68

Remarkably, as can be readily appreciated from FIG. 5D, thescale-dependent increase of the di-ester to boric acid ratio wasparticularly pronounced for a specific range of molar ratios, whilebeing less pronounced for other molar ratios. More specifically,scale-dependent increase of the di-ester to boric acid ratio wasespecially evident for the range of molar ratios between 1.8:1 and 2.2:1as is also reflected in Table 8 below.

TABLE 8 Molar Di-ester to Borate Ratio Ratio 200 ml 1 L 5 L 2000 L 1.43.61 3.68 4.25 1.6 5.91 6.63 7.25 1.8 9.91 10.63 12.63 2.0 9.05 13.3619.47 27.75 2.2 13.28 20.35 17.70

Notably, the di-ester to mono-ester ratio was substantially unaffectedby the increase in production scale as is reflected in FIG. 5E and theresults of Table 9 below.

TABLE 9 Molar Di-ester to Mono-ester Ratio Ratio 200 1000 5000 1.4 11.4512.32 8.60 1.6 10.55 10.42 8.67 1.8 10.89 10.37 11.77 2.0 12.58 10.5511.09 2.2 11.19 10.67 13.61

Exemplary pH values for various production scales shows the acidity tobe substantially uniform in the (mildly) acidic range, generally below7, in many cases below 6.5, and in most cases at or below 6 as can beseen from Table 10 below.

TABLE 10 Molar 1 L 5 L 2000 L Ratio pH pH pH 1.4:1 5.72 5.23 1.6:1 5.735.64 1.8:1 5.69 5.64 2.0:1 5.64 5.57 5.96 2.2:1 5.64 5.51

The inventors further investigated whether or not at least water removalfrom the finished reaction would further affect the product composition.Surprisingly, the inventors discovered that drying (e.g., viafreeze-drying “FD” and spray-drying “SD”) further dramatically increaseddi-complex to boric acid ratios in a substantially independent manner ofthe kind of water removal. Selected exemplary data are provided in Table11 below using a single molar ratio of 2:1 (fructose to boric acid) atthe listed production scales. Reconstitution was performed with D₂O tooriginal volume prior to water removal (i.e., at a dry ratio of betweenabout 2.2 to 3.5 by weight).

TABLE 11 2:1 Molar Ratio Only 200 ml 1 liter 5 liters Liquid FD SDLiquid FD SD Liquid FD SD dry ratio N/A 2.42 2.7 N/A 3.2 3.5 N/A 2.6 3.3Borate 9.28 5 4.7 6.4 4.3 4.1 4.5 3.7 3.9 Di-complex 84.04 86.9 86.985.5 86.2 87.9 87.6 86.5 87.1 mono-complex 6.68 8.1 8.4 8.1 8.5 8.6 7.99.9 9.3

FIG. 6A illustrates the change in di-complex to boric acid ratio as afunction of drying method for each of the production volumes, whileTable 12 below and FIG. 6B show the change in di-complex to boric acidratio as a function of production volumes for each of the dryingmethods.

TABLE 12 Ratio Di-complex to Borate 200 ml 1 liter 5 liters Liquid FD SDLiquid FD SD Liquid FD SD 9.06 17.38 18.49 13.36 20.05 21.44 19.47 23.3822.33

Thus, it should be noted that removal of water, and especially drying ofthe liquid compositions has the unexpected technical effect ofsubstantially increasing the di-complex to unreacted boric acid ratio,with a substantial increase of di-complex and a concomitant decrease inunreacted boric acid.

In some embodiments, the numbers expressing quantities of ingredients,properties such as concentration, reaction conditions, and so forth,used to describe and claim certain embodiments of the invention are tobe understood as being modified in some instances by the term “about.”Accordingly, in some embodiments, the numerical parameters set forth inthe written description and attached claims are approximations that canvary depending upon the desired properties sought to be obtained by aparticular embodiment. In some embodiments, the numerical parametersshould be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and parameters setting forth the broad scopeof some embodiments of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspracticable. The numerical values presented in some embodiments of theinvention may contain certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.Unless the context dictates the contrary, all ranges set forth hereinshould be interpreted as being inclusive of their endpoints andopen-ended ranges should be interpreted to include only commerciallypractical values. Similarly, all lists of values should be considered asinclusive of intermediate values unless the context indicates thecontrary.

The recitation of ranges of values herein is merely intended to serve asa shorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided with respectto certain embodiments herein is intended merely to better illuminatethe invention and does not pose a limitation on the scope of theinvention otherwise claimed. No language in the specification should beconstrued as indicating any non-claimed element essential to thepractice of the invention.

It should be apparent to those skilled in the art that many moremodifications besides those already described are possible withoutdeparting from the inventive concepts herein. The inventive subjectmatter, therefore, is not to be restricted except in the spirit of theappended claims. Moreover, in interpreting both the specification andthe claims, all terms should be interpreted in the broadest possiblemanner consistent with the context. In particular, the terms “comprises”and “comprising” should be interpreted as referring to elements,components, or steps in a non-exclusive manner, indicating that thereferenced elements, components, or steps may be present, or utilized,or combined with other elements, components, or steps that are notexpressly referenced. Where the specification claims refers to at leastone of something selected from the group consisting of A, B, C . . . andN, the text should be interpreted as requiring only one element from thegroup, not A plus N, or B plus N, etc.

What is claimed is:
 1. A method of producing a composition thatcomprises borocarbohydrate complexes in an amount of at least 65 wt %,wherein the borocarbohydrate complexes include di-complexes andmono-complexes, wherein the composition further comprises boric acid,and wherein the di-complex and the boric acid are present in a ratio ofat least 10:1, the method comprising: selecting a molar ratio between acarbohydrate and the boric acid of at least 1.8:1; selecting apreparative scale for the reaction of at least 1000 ml; and reacting thecarbohydrate with the boric acid under conditions and at the ratio andthe scale to form the carbohydrate complexes in an amount of at least 65wt % and at a di-complex to boric acid ratio of at least 10:1, andoptionally adding a cation to thereby form a salt of the carbohydratecomplexes.
 2. The method of claim 1 wherein the step of reacting formsthe carbohydrate complexes in an amount of at least 70 wt %.
 3. Themethod of claim 1 wherein the molar ratio between the carbohydrate andthe boric acid is between 1.8:1 and 2.4:1.
 4. The method of claim 1wherein the preparative scale for the reaction is at least 5,000 ml. 5.The method of claim 1 wherein the di-complex and the boric acid arepresent in a ratio of at least 15:1.
 6. The method of claim 1 whereinthe di-complex and the boric acid are present in a ratio of at least20:1.
 7. The method of claim 1 wherein the composition is a liquidcomposition.
 8. The method of claim 1 wherein the carbohydrate isfructose.
 9. The method of claim 1 wherein the cation is a calciumcation or a magnesium cation.
 10. The method of claim 1 further whereinthe composition has a pH of less than 6.0.
 11. A method of increasingdi-complex yield in a preparative reaction having a first reaction scaleto form a composition comprising at least 65 wt % borocarbohydratecomplexes, wherein the borocarbohydrate complexes are a mixture ofdi-complexes and mono-complexes, the method comprising: selecting amolar ratio between the carbohydrate and the boric acid of at least1.4:1; increasing the first reaction scale to a second reaction scale,and reacting the carbohydrate and the boric acid at the ratio at thesecond reaction scale effective to increase the di-complex yield in thesecond reaction scale as compared to the first reaction scale.
 12. Themethod of claim 11 wherein the carbohydrate is fructose.
 13. The methodof claim 11 wherein the first reaction scale is at least 200 ml andwherein the second reaction scale is at least 1,000 ml.
 14. The methodof claim 11 wherein the molar ratio between the carbohydrate and theboric acid is between 1.8:1 and 2.4:1.
 15. The method of claim 11further comprising a step of removing water from the composition.
 16. Ina method of producing a composition comprising borocarbohydratecomplexes and boric acid, wherein the borocarbohydrate complexes aremixture of di-complexes and a mono-complexes, the improvementcomprising: reacting a carbohydrate with boric acid at an acidic pH andat a molar ratio between the carbohydrate and the boric acid of at least1.8:1, wherein the step of reacting is performed at a preparative scaleof at least 1000 ml to produce a ratio of di-complex to residual boricacid of at least 8:1.
 17. The method of claim 16 wherein thecarbohydrate is fructose.
 18. The method of claim 16 wherein the pH isless than 6.0.
 19. The method of claim 16 wherein the molar ratiobetween the carbohydrate and the boric acid is between 1.8:1 and 2.4:1.20. The method of claim 16 wherein the ratio of di-complex to residualboric acid is at least 15:1.
 21. The method of claim 16 wherein theratio of di-complex to residual boric acid is at least 20:1.
 22. Themethod of claim 16 further comprising a step of removing water from thecomposition.
 23. A liquid composition produced by the method of claim 1comprising: a boron-containing fraction comprising a plurality ofborocarbohydrate complexes and boric acid; wherein the borocarbohydratecomplexes are a mixture of a di-complex and a mono-complex; and whereinthe di-complex is present in the boron-containing fraction of thecomposition in an amount of at least 75 wt %, wherein the boric acidconstitutes less than 13 wt % of the boron-containing fraction of thecomposition, and wherein a ratio of borocarbohydrate complexes tounreacted carbohydrate is at least 1.3 to
 1. 24. The liquid compositionof claim 23 wherein a ratio of the di-complex to the mono-complex in themixture is between 10:1 and 12:1.
 25. The liquid composition of claim 23wherein the di-complex is present in the composition in an amount of atleast 80 wt %.
 26. The liquid composition of claim 23 wherein thedi-complex is present in the composition in an amount of at least 85 wt%.
 27. The liquid composition of claim 23 wherein unreacted boric acidis present in the composition in an amount of less than 10 wt %.
 28. Theliquid composition of claim 23 wherein unreacted boric acid is presentin the composition in an amount of less than 5.0 wt %.